Quinoline compounds and process of making same



- UNITED STATES PATENT OFFICE QUINOLINE CDMPOUNDS AND PRBCESS OF :MAKING SAME Joseph H. 'Burckhalter, Detroit, Eldon M. Jones and Albert L. Rawlins, Grosse Pointe Woods, Frank H. Tendick, Grosse Pointe Park, and Walter F. Holcomb, Detroit, Mich., assignors to Parke, Davis & Company, Detroit, Mich., a corporation of Michigan No Drawing. Application November '5, "I945,-

Serial No. 626,908

15 Claims. (01; 260-286) 1 a 2 a n This invention relates to certain new and usewhere Z, r ,';R- and .Re ,have the same significance ful quinoline compounds and to methods for obas given above and X is a chlorine or bromine taining the same. More particularly, the invenatom. tion relates to quinoline compounds having the The reaction may be carried out by reacting formula, 5 approximately 'equimolar quantities of the i-haloquinoline and the substituted aminophenol in a suitable solvent. Such solvents are, in general, water, water-miscible organic solvents and water, water-miscible organic solvent mixtures.

Some of the water-miscible solvents which we may use are low molecular weight alcohols such as methanol, ethanol and ai-propanol, low molecular weight ketones such as acetone and methyl ethyl ketone, and 'ethers such as dioxane and eth- .ylen'eiglycol monoethyiether.

We prefer to carry out the above reaction in (lgwerlalkyb ...QH o -.a1ky1, r loweralkoxyy the presence of an sacidicwcatalyst. Such ca'tis One of the integers ,Qne, two, and three R alysts are dilute and concen-tratedorganic acids is hydrogen, halogen, lower alkylene or fi t F d P inorganic acidslower alkyl and R1 is hydrogen, an alkyl or al- Same the g am? winch, wewmay P kylene radical containing 1 to 10 carbon atoms are aceflcflpmpiomci Y f acldsinclusive a ,cyolohexyl radical When the reaction is carried out in the presence These new compounds am f l therapeutic of a. concentrated organ c acid, the acid serves agents and, in general, they are characterized by 9 the catalyst and as s T their toxicity to plasmodia. These compounds l e acids which We se are, in general, mm-

may be used either in the form, of their bases eral ac ds such as hydrochloric, hydrobromic, sulor their salts with organic or inorganic acids such fume phfliwmmnd like acidsas hydrochloric acid, sulfuric acid, phosphoric A fi ii of our w for obtammg acid, sulfamic acid, acetic acid, lactic acid, tar- WWW 'Fm m M an taric acid, gluconicacid, citric acid and alkyl sul- 3 3 y f n a' j the msmuufd 'a j P e fonic acids or as the insoluble salt of methylene In l m m ih'e'aqy'l flenva'twe t hydro disancync acm *lyaed to the aromatic amine under acidic con- This application is a continuation in-part of Q fim the amme SD firmed F'aus'ed i our copending'applicatiomSerialNo. 539,990,,flled s m t w s' i fl with the -m June 12, .1944, now U. s. Patent No. 2,428,355, is- .quin'blme compound. This is illustrated by the suedoct 7 1,947 following two equations employing the acetyl The compounds of the present invention may derivative the Substituted aminbphenol be prepared by the reaction of a substituted amir "1] nophenol of the formula, 1 T

where Z, n, R, R1 and X have thesame significance as given above. f

The invention is illustrated by the following examples.

Example 1.-4 (3' etliylaminomethyl 4' droxyamlino) 7-ch-loroqui nol ine NE on OHQCHB HaN A mixture consisting of 18.5 g. of 2-ethylaminomethyl-4-aminophenol dihydrochloride and g. of 4,7-dichloroquinoline in 100 cc. of methanol is refluxed for three hours. The reaction mixture is concentrated to one-half volume, cooled and the dihydrochloride salt of the desired 4-(3- ethylaminomethyl-4-hydroxyanilino) -7- chloro quinoline removed by filtration. The crude salt is purified by recrystallization from absolute ethanol; M. P. 280 C. dec.

Example 2.4-(3'-n-butylaminomethyl- 4' hy droxyam'l-ino) -7-chloroquinoline NH OH HzN o1 oruomomom 23.6 g. of 2-n-butylaminomethyl-4-acetylami nophenol is refluxed for one hour with 50 cc. of 6 N hydrochloric acid, The solution is cooled and the pH adjusted to about 4 by the addition of dilute sodium hydroxide solution. 19.5 g. of 4,7- dichloroquinoline is added and the mixture refluxed for one and a half hours. After cooling,

the mixture is made just alkaline with sodium hydroxide solution, the precipitate base'reinoved by filtration and washed with water and dried. The base is dissolved in methanol and an excess of alcoholic hydrogen chloride added. Acetone is added to precipitate'the'product, the product collected and purified by recrystallizatio fr0m methanol-acetone mixture.

Example 3.4-(3-n-amylaminomethyl- 4' a hy droxyanilino) -7-chl0roquinoline oi omomcmomom am. H,

26.2 g. of 2-n-amylaminomethyl-4-acetylaminophenol is heated with 60 cc. of 6 N hydrochloric acid on a steam bath for one and a half hours. The solution is diluted with water and made just acid to Congo red by the addition of sodium hydroxide solution. 20.? g. or 4,7-dichloroquinoline is added and the mixture refiuxed for forty minutes. The yellow product starts to separate soon after refluxing is started. The mixture is treated with 2 or 3 cc. of concentrated hydrochloric acid and the mixture cooled. The solution is decanted from the crude solid dihydrochloride and the residue taken up in methanol. The solution is filtered, evaporated and the product precipitated by the addition of acetone. The pale yellow crystalline dihydrochloride is collected and purified further by recrystallization from ethanol; M. P. 266 C. dec.

Example 4.-4-(3'-a-hexylammomethyl-4' hy droxyam'lino) -7-chloroquinoline NHQ- O H I i H HQN/ Cl CH2OH2OH2CH2CHZCH3 A mixture consisting of 52.5 g. of Z-n-hexylaminomethyll-acetylaminophenol, 35 cc. of concentrated hydrochloric acid and 50 cc. of alcohol is refluxed for one hour, cooled and the pH of the solution adjusted to about 4 by the addition of dilute sodium hydroxide solution. 39.4 g. of 4,7- dichloroquinoline is added, the mixture refluxed for two hours, cooled and the sodium chloride removed by filtration. Acetone is added to the filtrate, the crude dihydrochloride which separates collected and purified by recrystallization from methanol-ethanol mixture; M, P. 280 C. dec.

Example 5.-4-(3'-n-heptylaminomethyl-4'- hydrozvyanilino) -7-chloroquinoline 43 g. of 2-n-heptylaminomethyl-4-acetylaminophenol is refluxed with 100 cc. of 20% hydrochloric acid for one hour, cooled and the pH of the solution adjusted to about 4 by the addition of 40% sodium hydroxide solution. 30.8 g. of 4.7-dichloroquinoline and 200 cc. of dioxane are added and the mixture refluxed for three hours. The solution is cooled, made alkaline with ammonium hydroxide and diluted to a volume of one liter with water. Themixture is shaken with chloroform, the chloroform extract filtered, washed with water and the extract dried. The chloroform is distilled and the residue taken up in alcoholic hydrogen chloride, On the addition of ether to the hot solution the crude dihydrochloride of the product separates. The salt is collected, washed with ether-and purified by recrystallization from ethanol; M. P. 280 C. dec.

Example 6.4- (3'-n-octylaminomethgjl-4- hydrozcyanzlino) -7-chloroquinoline CHzCHzCHgCHgCHgCHzCHnCHa 36.8 g. of 2-n-octylaminomethyll-acetylaminophenol is refluxed with 200cc. of water and 25 cc. of concentrated hydrochloric acid for one hour, cooled and the solution made just acid to Congo red by the addition of sodium hydroxide solution. 24 g. of 4,7-dichloroquinoline is added, the mixture refluxed for one hour and cooled. The crude hydrochloride which separates is removed by filtration, washed with water and dissolved in ethanol. The alcoholic solution is flltered, evaporated and the product caused to crystallize by adding acetone. The crude dihydrochloride is separated and treated with an excess of dilute sodium hydroxide solution. The mixture is extracted with ether, the ether extract Washed and the ether distilled. The residue which consists of the desired free base is purified by recrystallization from ethanol or from ethanol-ether mixture; M. P. 150 C.

Example 7.--4- (3'-a-methylallylaminomethyl-4'- hydroxyanilz'no) -7-chloroquinolz'ne 132.5 g. of 2-amethylallylaminomethyll-acetylarninophenol is refluxed with 200 cc. of ethanol and 50 cc. of concentrated hydrochloric acid for one and a half hours. The pH of the solution is adjusted to about 4 bythe addition of dilute sodium hydroxide solution. chloroquinoline is added, the mixture refluxed for two hours, cooled and the sodium chloride which separates removed by filtration. Acetone is added to the alcoholic filtrate and the crude dihydrochloride of the product which separates removed by filtration. The crude product is purified by recrystallization from methanol-ethanol mixture.

Example 8.4-(3-cyclohe:cylamin0methyl-4- hydrowyam'lino) -7-chloroquinolz'ne 110.8 g. 0f 4,7-di- Example 9.4-(3'-iso-butgjlaminomethyl-4'- hydromyamlz'no) -7-chloroquinoline 23.6 g. of 2-iso-butylaminomethy1-4-acetylaminophenol is refluxed for one hour with cc. of 6 N hydrochloric acid. The solution is cooled and the pH adjusted to about 4 by the addition of dilute sodium hydroxide solution. 19.5 g. of 4,7-dichloroquinoline .is added and the mixture refluxed for one and a half hours. After cooling, the mixture is made just alkaline with sodium hydroxide solution, the precipitated base removed by filtration and washed with water and dried.

The base is dissolved in methanol and an excess of alcoholic hydrogen chloride added. Acetone is added .to precipitate the product, the product collected and purified by recrystallization from methanol-acetone mixture.

Example 1 0.3-methyl-4- (3' -n-heptylaminomethyl-l-hydroztyunilino) -'7-chloroquinoline Example 1.1.4--(2-bromo4-ethylamino-5hydroryanilino.) 6,7-dimethylquinoline 28 g. of 2-ethylamino-4-bromo-5-acetylaminophenol is refluxed with lone. of -.6 N hydrochloric acid for one hour, cooled and the pH of the solution adjusted to about 4 by the addition of dilute sodium hydroxide solution. '20 g. of 4-chloro- 6,7-dimethylquinoline is added and the mixture refluxed for one and a half hours, cooled and the solution made just alkaline with dilute sodium hydroxide solution. The mixture is extracted with chloroform, the chloroform extract washed with water, dried and the chloroform distilled. The residue taken up in a small amount of alcohol. treated with an excess of hydrogen chloride in alcohol and the dihydrochloride of the product precipitated by the addition of acetone. Thebrude :dihydrochloride salt OH CHzN OHzCHs IFH 24 g. of 4-chloro-8-bromoquinoline is added to a solution of 20 gxof 2-ethylaminomethyl-4- chloro--6-arninophenol in 65 cc. of water acidified to pH 4 with hydrochloric acid and the mixture refluxed for one and a half hours. The mixture is' cooled, made just alkaline with sodium hydroxide solution and extracted with chloroform. The chloroform extract is washed with water, dried and the chloroform distilled. The residue is taken up in methanol, the solution treated with an excess of dry hydrogen chloride in methanol and the crude dihydrochloride precipitated by the addition of acetone. The product is collected and purified by recrystallization from methanol-acetone mixture. Example 1 3.4- (3 -n-butylaminomethyl-4" -hydraw-5 -allyiam'lino) -7-hydroxyquinoline 23.4 gof 2-n-butylaminomethyl-4-amino-5- allylphenol dihydrochloride is added to a solution of 17.8 g. of l-chloro-5-hydroxyquinoline dissolved in 200 cc. of n-propanol and the resulting mixture heated under reflux for two hours, cooled and the mixture treated with water. About 5 cc. of concentrated hydrochloric acid is added and the solution extracted exhaustively with ether. The ether extracts are discarded and the mixture made just alkaline with ammonium hydroxide solution. The alkaline solution is extracted with ether, the ether extract washed, dried and then treated with an excess of dry hydrogen chloride. The crude dihydrochloride which separates is collected and purified by recrystallization from methanol-acetone mixture.

Example 14.-4- (2',4-dihydroa:y-5-ethylaminomethylamlz'no) -5-chloro-8-methoxyquinoline (11 NH -OH N/ CHgCHz 22.4 g. of 2,4-dihydroxy-5-ethylaminomethyl acetanilide is refluxed with 25 cc. of 6 N hydrochloric acid and 60 cc. of alcohol for one hour. The solution is cooled and the pH adjusted to about 4 by the addition of 30% sodium hydroxide solution. 22.5 g. of 4,5-dichloro-8-methoxyquinoline is added and the mixture refluxed for one and a half hours, cooled and the sodium chloride removed by filtration. Acetone is added to solu- 8 tion and the crude dihydrochloride salt which separates removed by filtration. The crude product is purified by recrystallization from methanol-acetone mixture.

5 Example 15. 3 carboethomy-4-(3'-methyZ-4'- hydromy-S'-aminomethylanilino) G-methoryquinoline V CHaO C O O CaHa HzNHz A mixture consisting of 22.5 g. of 2-aminomethyl--amino 6 methylphenol dihydrochloride and 26 g. of 3-carboethoxy-4-chloro-6-methoxyquinoline in 300 cc. of absolute ethanol is refiuxed for two hours, cooled and the crude dihydrochloride cf the product precipitated by the addition of acetone. The solid is collected and purified by recrystallization from ethanol-acetone mixture.

Attention is directed to our copending applications Serial No. 556,496, filed Sept. 29, 1944; Serial No. 576,900, filed Feb. 8, 1945; Serial No. 626,907, filed Nov. 5, 1945; and Serial No. 722,474, filed Jan. 16, 1947, wherein somewhat related quinoline compounds are described and claimed. Attention is also directed to our copending application Serial No. 626,906, filed Nov. 5, 1945, wherein certain quinoline compounds falling within the scope of the-instant claims are claimed and an alternative process for preparing the compounds of the instant case is described and claimed.

What we claim as our invention is:

1. A compound of the class consisting of a free base and its acid addition salts, said free base having the formula,

cals containing 1 to 10 carbon atoms inclusive, the group R1 CH2N/ being attached to the aryl nucleus in one of the positions ortho and para to the hydroxyl group.

2. An acid addition salt of a compound having the formula,

3. acid addition salt of acompound having theformula,

4. An acid, addition salttoftacompound having the formula,

CEzCHgCHzCHg 6. A compound of the formula,

NH OH l H HZN ol -(I CHzCHCHa 7. A compound of the formula,

NH -0H I H L'HQN 01- \N% cmomornomomom 8. Process for obtaining a compound of the formula, OH B NH LCHZN/ l- Rl which comprises reacting a i-haloquinoline compound of the formula,

with a substituted aminophenol of the formula,

lOH H :-Cl-IzN .T NH:

where X is a member of the class consisting of chlorine and bromine, Z is a member of the class consisting of hydrogen, halogen, -COO- (lower alkyl), OH, lower alkyl and lower a1- korw radicals, n is one of the integers consisting of one and two, R is a member of the class consisting of hydrogen, halogen, OH, lower alkenyl and lower alkyl' radicals and R1 is a member of the class consisting of hydrogen, cyclohexyl, a1- kyl radicals containing 1 to 10* carbon atoms inclusive and alkenyl radicals containing 1 to 10 carbonatoms inclusive, the group /R1 CHQN being? attached to the aryl nucleus ilm-onesof the positions ortho and para to the hydroxyl. group.

9. Process for obtaininga compound of the formula,

l-on H TCHaN TR Rt which comprises reacting a 4-haloquinoline compound of the formula,

NHn

in the presence of an acid, where X is a member of the class consisting of chlorine and bromine, Z is a member of the class consisting of hydrogen, halogen, --COO(lower alkyl), lower alkyl and lower alkoxy, n is one of the integers consisting of l and 2, R is a member of the class hydrogen, halogen, OH, lower alkenyl and lower alkyl radicals and R1 is a member of the class consisting of hydrogen, cyclohexyl, alkyl radicals containing 1 to 10 carbon atoms inclusive and alkenyl radicals containing 1 to 10 carbon atoms inclusive, the group R1 omN being attached to the aryl nucleus in one of the positions ortho and para to the hydroxyl group.

10. Process for obtaining a compound of the which comprises reacting 4,7-dichloroquinoline with Z-n-butylaminomethyl 4 aminophenol in the presence of a dilute mineral acid.

11. Process for obtaining a compound of the formula,

IITH OH l HQN Cl M CHSCHCHS which comprises reacting 4,7-dichloroquinoline with 2-isobutylaminomethyl 4 aminophenol in the presence of a dilute mineral acid.

12. Process for obtaining a compound of the formula,

NH OH H fiiN C1 CHgCHzCHiCHgCHgCHa which comprises reacting 4,7-dichloroquinoline with 2 n hexylaminomethyl-4-aminophenol in the presence of a dilute mineral acid.

- 12 13. A hydrohalide salt of 4-[3'-n-butylaminomethyl-4-hydroxyanilinol-7-chloroquinoline.

14. A hydrohalide salt of 4-[3isobutylaminomethyl-4'-hydroxyanilino] -7-chloroquinoline.

15. A hydrohalide salt of 4-[3'-n-hexylaminomethyl-4-hydroxyanilinol -7 -chloroduinoline.

JOSEPH H. BURCKHALTER. ELDON M. JONES.

ALBERT L. RAW'LINS. FRANK H. TENDICK. WALTER F. HOLCOMB.

REFERENCES CITED The following referenlces are of record in the file of this patent:

UNITED STATES PATENTS Number Name Date 1,891,980 Hartman Dec. 27, 1932 1,896,461 Muth Feb. '7, 19.33 1,902,103 Schonhofer Mar. 21, 1933 

